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Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 1 of 11. Date: March 28, 2012 Chapters 14.8, 23-1,2, 5, and 7: Carbohydrates - Part II
II. Glycosides – A general term used to describe organic molecules covalently bound to carbohydrate molecules (through anomeric bonds).
(1) Formation of glycosides
O
HOHO
HO OH
OCH3
H
HH HO
OH HO
HOO
HOHO
HO
OH
HO
12
4
3
5
6
1
anomeric carbonanomeric carbonβ-anomerα-anomer
C1-epimers; anomers; diastereomers
CH3OH, 0.7 % HCl, 10 °C (short time)
HO HCH2OH
H
OCH3
HH HO
OH HOHO H
CH2OH
23
4
5
6
1+
β-anomerα-anomer
methyl α-D-glucofuranoside methy β-D-glucofuranoside
anomeric carbonanomeric carbon
1
O
HOHO
HO OCH3
HO
O
HOHO
HO
OCH3
HO
12
4
3
5
6
anomeric carbonanomeric carbonβ-anomer
α-anomer
1
CH3OH, 4 % HCl, rt
methyl α-D-glucopyranoside methyl β-D-glucopyranoside
Kinetic conditions (for this reaction)!
Thermodynamic conditions!
MAJOR PRODUCT MINOR PRODUCT~66%~33%
+
In general, (5-membered) furanosides are formed preferentially under the kinetic conditions, whereas (6-membered) pyranosides are formed under the thermodynamic conditions, i.e., more stable. Five membered systems have a number of eclipsing interactions, thus less stable.
Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 2 of 11. Date: March 28, 2012
(2) Mechanism for the formation of anomeric glycosides
O
HOHO
HO O
HO
O
HOHO
HO OH
HO
12
4
3
5
6
anomeric carbonβ-anomer
1
When protonation occurs on the anometic OH. O
HOHO
HO O
HO
1
H
H
O
HOHO
HO
HO
1
lone pair-assisted ionization.
HO CH3
or
When protonation occurs on the ether oxygen atom.
H
HO
HOHO
HO O
HO H
H
H
HO CH3
or
lone pair-assisted ionization.
1
O
HOHO
HO
HOH
HOH
O CH3
H
stereochem. mixture
HO CH3
1
O
HOHO
HO
HOH
HO
O CH3
H H
O CH3H
1
O
HOHO
HO
HOH
HO
O CH3
H
H
lone pair-assisted ionization.
1
O
HOHO
HO
HOH
H
O CH31
O
HOHO
HO
HOH
H
OCH3
O
HOHO
HO OCH3
HO
1O
HOHO
HO
OCH3
HO
O
HOHO
HO OCH3
HOO
HOHO
HO
OCH3
HOH H
H
H
H
H
HO CH3
HO CH3
β-anomer α-anomer
rotation along the C1-C2 bond
2
Comments: • The α-anomeric hemiacetal undergoes similar processes to produce a mixture of anomeric glycosides. • Protonation on the lone pairs of the oxygen atoms other than the anomeric (i.e., C1-O) and ether ring oxygen ones does not lead to the ready elimination of the protonated hydroxyl groups due to the lack of the lone pair-assisted ionization.
Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 3 of 11. Date: March 28, 2012
(3) Hydrolysis of the Glycosidic Linkages a. Lactose – milk sugar; disaccharide; reducing sugar (one hemiacetal group)
O
HOHO
HO OH
1'
2'4'
3'
5'
6'anomeric
carbon
β-glycosidic linkage (or bond)
O
HO
HO OH
OH
1
6
54
3
2
anomeric carbon
hemiacetal
β-D-lactose reducing sugar
O
HOHO
HO OHO
HOHO OH
OH4
OH
anomeric mixture
+H3O+
D-galactoseanomeric mixture
D-glucose
H
NaOH (excess), (CH3)2SO4 (excess)
NaH (excess), CH3I (excess)or
permethylation with
O
H3COH3CO
H3CO OCH3
1'
2'4'
3'
5'
6'
O
H3CO
H3COOCH3
OCH3
1
6
54
3
2
H3O+ O
H3COH3CO
H3CO OCH3O
H3COH3CO OH
OCH34
OH +
All glycosidic bonds get hydrolyzed
2,3,4,6-tetra-O-methyl D-galactose
2,3,6-tri-O-methyl D-glucose
Taken together, D-lactose must be: (D-galactose)-O-(D-glucose) attached at the C4-OH of D-glucose; O-β-D-galactopyranosyl-(1->4)-β-D-glucopyranose or β-D-Galp-(1->4)-β-D-Glcp. This reaction concept can be used for sequencing polysaccharides.
terminal sugar!4-OH is free. Thus,the other sugar is attached to the C4-OH.
All OHs except the anomeric OH methylated.
H
b. Sucrose (“Sugar”): disaccharide; non-reducing sugar (no anomeric hemiacetal nor hemiketals)
O
HOHO
OH
HO
D-glucose CH2OH
HCH2OH
OH H
HHO
O
1
2
3 4
5
6
O
HOHO
OH
HO
D-glucose(anomeric mixture)
OH
CH2OH
HOH2C
OH H
HHO
O
1
2
345
6
H3O+CH2OH
HOH2C
OH H
HHO
O1
2
345
6
OH
D-fructose(anomeric mixture)
+
β-glycosidic linkageto fructose
α-glycosidic linkageto glucose
Both of these are reducing sugars!O
HOHO
OH
HOD-glucose
β-glycosidic linkageto fructose
α-glycosidic linkageto glucose
D-fructose
D-fructose
Sucrose:O-β-D-fructofuranosyl-(21)-α-D-gluco-pyranoside or β-D-Fruf-(21)-α-D-Glcp
f: furanosyl; p: pyranosyl
H H+
Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 4 of 11. Date: March 28, 2012
III. The Anomeric Effect: The inherent preference of electronegative substituents (usually OR, SR or halogen atoms) for the axial position at the anomeric carbon; largest for halogen atoms.
See: Juaristi, E.; Cuevas, G. The Anomeric Effect; CRC Press: Boca Raton, FL; 1995. Examples: (1)
O
O
X
X ____________________________________________ X = Cl ΔG° 1.8 kcal/mol Br 1.8 OCH3 0.9 OCH2CH3 0.8 SCH3 0.5 OH -0.3 ~ -0.1 NHCH3 -0.9
11% 89%
ΔG°25°C = -1.24 kcal/mol
Note:
OH
OH
(2)
O
HOHO
HO OH
HOO
HOHO
HO
OH
HO
124
3
5
6
1
64%36%
ΔG°25°C = -0.34 kcal/mol
So, the inherent anomeric effect (AE) for an OH may be estimated to be: AE (OH) = ΔG° (pyranose) - ΔG° (cyclohexane) = -0.34 – (-1.24) = 0.90 kcal/mol
Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 5 of 11. Date: March 28, 2012
Explanations for the Anomeric Effect
(1) Repulsive lone pair-lone pair interactions:
OO
CH3H
equatorial
axial equatorial
OH
O
axialequatorial
CH3
1
25
1
25
Stays away from the ringportion, avoiding the steric repulsion.
3
HH
1,3-diaxialinteractions
View through theC1 - ring O bond
View through theC1 - ring O bond
Equatorial C1-OCH3 Axial C1-OCH3(stabler)
Ring oxygen
C5H
OC2C1
axial
CH3
equatorialrepulsivelone pair-lone pairorbital interaction!
repulsive lone pair-lone pairorbital interaction!
Ring oxygen
C5O
HC2C1
axial
equatorial
repulsivelone pair-lone pairorbital interaction!CH3
Only one bad interaction!! (2) The hyperconjugative orbital interaction concept
axialAxial C1-OCH3(stabler)
axial
OH
OCH3
12
5C1-OCH3
σ∗n
anti-bonding orbitals
hyperconjugative, stabilizing orbital interaction:the oxygen lone-pair electrons are delocalizing into the antibonding C1-O orbital (σ* orbital) of the axial C1-O bond.
C1-OCH3σ∗
n
FMO interpretation
This hyperconjugation should make the C1-O bond shorter and the C-X bond longer.
O
Cl
O
Cl1 1 hyperconjudation
1
O
Cl
1
Bond length comparisons:
OCl
1
OCl
1.43Å 1.82Å1.39Å
1.72Å 1.43Å 1.78Å
OO
Cl
11.82Å1.39Å
Cl
Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 6 of 11. Date: March 28, 2012
Reactions of Carbohydrates (1) Isomerization of sugars: usually in the presence of acid or base
OHHHHOOHHOHH
CH2OH
OH
D-glucose
open chain form "ene-diol"
epimer
ketose
1
2
3OHHHOOHHOHH
CH2OH
OHH 1
23
HHOHHOOHHOHH
CH2OH
OH
D-mannose
1
2
3
OHHOOHHOHH
CH2OH
OHH
D-fructose
123"ene-diol"
H
OOH
HOHO
OH
HO
12
4
3
5
6
C2-epimer of D-glucose
O
HOHO
HOOH
HO
124
3
5
6
CH2OHHOH2C
OH H
HHO
O1
2
34
5
6
OH
OHHHHOOHHOHH
CH2OH
OH
D-glucose
1
2
3
HHOHHOOHHOHH
CH2OH
OH
D-mannose
1
2
3
OHHOOHHOHH
CH2OH
OHH
D-fructose
123
H
OOH
HOHO
OH
HO
12
4
3
5
6
C2-epimer of D-glucose
O
HOHO
HOOH
HO
12
4
3
5
6
CH2OHHOH2C
OH H
HHO
O1
2
34
5
6
OH
Under base-catalyzed conditions
D-glucose
NaOH (0.04%)
H2O, 35 °C50 h
(~69%)
(~1%)
(~20%)
+
+
Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 7 of 11. Date: March 28, 2012
OHHHHO
OH 12
3
HOOH
HHO
OH 1
3
2HO
H
HHOHHO
OH 12
3
Protonation at C2 from the bottom faceglucose
mannose
HO
Hb
a
aa
b
OHHO
OHH 1
3
2
H
"ene-diol"
OH
a
OHHO
OHH1
3
2
H
OH
OHHOOHHOHH
CH2OH
OHH1
23
H
D-fructose
Mechanism:
Protonation at C1
b
--------------------------------------------------------------------------
OHHHHO
OH 1
2
3OHHHHO
OH 12
3
H
H2O
OHHHO
OH 1
3
H
H2O
2
HO
H
H
HO
H
H
HHOHHO
OH 12
3
H
HHOHHO
OH 12
3
Protonation at C2 from the bottom face
Protonation at C1Loss of H+C=O
(fructose)
glucose
mannose
Mechanism under H3O+ conditions
(2) Reducing sugars: Sugars that contain a hemiacetal or hemiketal, and are therefore in equilibrium with open form, are called “reducing sugars.”
O
HOHO
HOOH
HO
1
OHHHHOOHHOHH
CH2OH
OO 1
OHHHHOOHHOHH
CH2OH
OH 1
2
3Ag2O
NaOH/H2O Ag0 (silver mirror)+
Also, with Cu2+ (CuSO4) [deep blue color]/NaOH [Benedict's reagent] reducing sugarCu2O (Cu+1) [red ppts]
Tollens test
Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 8 of 11. Date: March 28, 2012 (3) Oxidation reactions involving C1-OH or C1- and C6-OHs (a) Br2 in H2O oxidizes only aldoses
O
HOHO
HOOH
HO
1
OH
HOHO
HO
HO
OH
OH
HOHO
HO
HO
OOH O
HOHO
HO
HO
O
Br2 + 3 H2O
+ 2 Br- + 2 H3O+
H3O+
note: Br2 + H2O HBr + HOBr
Under the acidic conditions, this hydroxy acid closes to form the six-membered lactone.
(b) HNO3 oxidation: HNO3 is a stronger oxidizing agent than Br2–H2O, oxidizing both the aldehyde group and the terminal –CH2OH of an aldose to the corresponding di-acid.
OHHHHOHHOOHH
CH2OH
OH
D-galactose(optically active)
1
2
3
4
5
6
OHHHHOHHOOHH
OHO
galactaric acid(meso; optically
inactive)
1
2
3
4
5
6
O OH
HNO3, Δ
Both C1 and C6 ends get oxidized to COOH's.
(4) Both (hemiacetal) aldoses and (hemiketal) ketoses undergo reactions observed for aldehydes and ketones, respectively.
O
HOHO
HOOH
HO
1OHHHHOOHHOHH
CH2OH
OHHHHOOHHOHH
CH2OH
OH 1
2
3 HCN
H2O
H OHC N
OHHHHOOHHOHH
CH2OH
HO HC N
* * *
+
CH2OHOHHOOHHOHH
CH2OH
D-fructose
1
23CH2OH
OH H
HHO
O1
2
34
5
6
OH
HO
α-/β-D-fructofuranose
CH2OHOHHHOOHHOHH
CH2OH
1
2
3
CH2OHHHHOOHHOHH
CH2OH
1
2
3NaBH4CH3OH-H2O
H HO+
Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 9 of 11. Date: March 28, 2012 (4) Reactions of hydroxyl groups and their derivatives
Selective reactions of anomeric OHs and their derivatives under acidic conditions (by an SN1 process) and glycoside formation of the anomeric bromide (by an SN2 process).
(a)
O
H3COH3CO
H3CO
OCH3
H3CO
1O
H3COH3CO
H3CO
H3CO
1O
H3COH3CO
H3CO
Br
H3CO
1
HBr(gas)
CH2Cl2
BrSN1
KO-CH2Ph
O
H3COH3CO
H3CO
H3CO
1O
CH2Ph
+ KBr
SN2 !The α-bromide formed due mainly
to the anomeric effect of Br.
(b)
O
HOHO
HO
HO
1O
OO
O
O
O
1
CH3
OCH3
H3C
H3C
H3C
OO
OO
OH
H3C O CH3
O O
N
(excess)
O
OO
O
Br
O
1
CH3
H3C
H3C
H3C
OO
OO
OH
O
OH
HO
HBr (gas)acetic acid
(0 °C)
KOH, ΔK
O
OO
O
O
1
CH3
H3C
H3C
H3C
OO
OO
OH
OSN2
SN1
O
OHHO
HO
HO
1
OH
O
salicin
NaOH-H2O
more acidic
+ KBr
H3C O CH3
O O
N
H3C O CH3
O O
N
H3C O
N
*
*
O
H
H3C OR
O
R
Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 10 of 11. Date: March 28, 2012 Summary of Carbohydrate Reactions The reactions applied to carbohydrates are not new and have been covered in earlier chapters, but they often exhibit uniquely carbohydrate behaviors. 1. Base or acid-catalyzed isomerization between aldoses and ketoses via ene-diol intermediates, particularly the mechanism. 2. Reactions of aldoses/ketoses with those that react with an aldehyde or ketone C=O group such as NaBH4/CH3OH and a primary amine, NH2R. 3. Acid-catalyzed reactions at the anomeric center of a carbohydrate, particularly the mechanism that involves the lone pair-assisted ionization. 4. Ether formation from ROH: R’X/NaH or (CH3)2SO4/NaOH 5. Acylation of ROH:
6. Selective reactions of a primary alcohol with electrophiles For example,
For the deprotection of the trityl group [Ph3C-], mild acidic conditions such as aq CF3C(=O)OH are used.
7. Hydrolysis (with HO-) [see p 9 (b) of Carbo notes Part II] or methanolysis (NaOCH3/CH3OH) of esters such as acetates. For example,
Chem 215-216 HH W12 Notes – Dr. Masato Koreeda - Page 11 of 11. Date: March 28, 2012 8. SN2 reactions of mesylate, tosylate, and triflate [OTf; trifluoromethanesulfonate, OS(O)2CF3] derivatives of primary and secondary hydroxy groups. For example,
9. Acetal/ketal derivatives of diols and their hydrolysis. For the formation of acetal/ketal derivatives, RR’C(OCH3)2 [such as Ph-CH(OCH3)2] is usually used especially when a sugar has 1-OR group, instead of an aldehyde [e.g., Ph-C(=O)H] or ketone [e.g., (CH3)2C=O]. This is to avoid the hydrolysis of 1-OR by the water generated as a result of acetal/ketal formation from a diol when a RR’C=O is used. Preferred formation of acetals/ketals from 1,2-cis-diol
The acetal/ketal derivative of a trans-diol is considerably more strained compared with those formed from cis-diols.
When there is no cis-diol in the pyranose ring, the six-membered acetal/ketal involving 4- and 6-OH’s is formed.